Transvaginal drug delivery is a well known means of administering drugs to a female (Woolfson, A. D., Malcolm, R. K. and Gallagher, R. (2000) Critical Reviews in Therapeutic Drug Carrier Systems 17:509–555). The transvaginal route has several advantages: (1) it is non-invasive; (2) the vagina consists of highly perfused tissue with a well-developed blood supply; (3) it avoids first-pass metabolism in the liver. The transvaginal route may be used both for local drug treatment as well as systemic drug absorption.
Transvaginal drug delivery systems may be classified in two main groups: those adapted from semisolid topical systems and those designed specifically for intravaginal use. Known systems include the following:                Mucoadhesive gels and hydrogels. These are weakly crosslinked polymers which are able to swell in contact with water and spread onto the surface of mucus. These have been used for cervical ripening, spermicidal contraception, vaccination and treatment of vaginal infections;        Vaginal tablets. They may be formulated with mucoadhesive polymers in order to increase intravaginal residence time. They have been used for cervical ripening, spermicidal contraception, pregnancy termination, analgesia and urge incontinence;        Vaginal pessaries and suppositories. These are substances such as natural gums, fatty acids, alum and rock salts which were originally used by the ancient Egyptians as contraceptives. They have been used for cervical ripening, treatment of vaginal infections, pregnancy termination and progesterone therapy;        Microspheres for the delivery of peptide and protein drugs;        Intravaginal rings. These are torus-shaped polymeric devices designed to release one or more incorporated drugs in a controlled fashion. They have been used for steroidal and spermicidal contraception, and estrogen replacement therapy.        
U.S. Pat. No. 3,918,452 (Cornfeld) discloses vaginal sponges and/or tampons impregnated with contraceptive compositions. The composition comprises microcapsules containing a contraceptive drug and which provide sustained release of the drug before, during and/or after coitus.
U.S. Pat. No. 4,309,997 (Donald) discloses a medicated tampon in the form of a soft, porous foam ball of spherical configuration. The tampon is as impregnated with a contraceptive drug and/or an antibiotic for control of venereal disease. The tampon is inserted into the vagina to cover the cervical area while permitting intercourse to take place.
U.S. Pat. No. 5,201,326 (Kabicki et al) discloses a rod-shaped medical tampon for releasing an active substance. The tampon includes a core of compressed fibers an a cover surrounding the core and glued thereto, the cover comprising hardened collagen foam or hardened gelatin foam impregnated with a retardant, such as a fatty substance, including the dissolved active substance to be released. The active substance may be antibiotics, sulfonamides, antimycotics, fungicides or hormones. U.S. Pat. No. 5,417,224 (Petus et al) discloses a tampon comprising a porous spherical member having an inner region configured radially within an outer region, a cord extending through a passage extending through the spherical member, a spermicide within the pores of the inner region and a lubricant within the pores of the outer region.
U.S. Pat. No. 6,086,909 (Harrison et al) discloses devices and methods for the treatment of dysmenorrhea which comprise an intravaginal drug delivery system containing an appropriate pharmaceutical agent which is released into the vagina and absorbed through the vaginal mucosa via lymphatic and venous channels to the uterus. The drug delivery system may include a tampon device, vaginal ring, pessary, tablet, vaginal suppository, vaginal sponge, bioadhesive tablets, bioadhesive microparticle, cream, lotion, foam, ointment, solution or gel. The system may additionally include a muco-adhesive agent and/or a penetration enhancer. In the case where the device is an absorbent vaginal tampon, one end of the tampon has a means for delivering the pharmaceutical agent while the other end has means for conveying fluid discharged from the uterus (such as menses fluid) to the tampon, thereby preventing contact of the fluid with the agent.
Non-steroidal anti-inflammatory drugs (NSAID) are marketed worldwide as over the counter (OTC) analgesics and antipyretics, of which, the most commonly used are aminophen, aspirin, ibuprofen and naproxen.
The mechanism of most anti-inflammatory, antipyretic and analgesic effects of NSAIDs result from the inhibition of prostaglandin synthesis from arachidonic acid. The target of NSAID action is PGHS, which is the key rate-limiting enzyme in the production of prostanoids. This enzyme catalyzes the conversion of arachidonic acid to PGH2 via a two-step reaction mechanism involving sequential cyclooxygenase and peroxydase activities.
Generally, OTC analgesics are regarded as safe for the majority of patients. However, adverse effects have been reported and are mainly associated with the oral administration of NSAIDs, occurring mostly in the gastrointestinal tract. Dyspepsia appears to be the most common side effect, but serious adverse effects such as bleeding, ulceration and perforation can also occur. The potential of adverse renal effects have also been reported, although for some NSAIDs this relationship remains controversial. Most adverse renal effects, however, are reversible on prompt discontinuation of the analgesics.
Numerous studies have dealt with the controlled release of NSAIDs from capsules, matrices, or gels. Colloidal liposomal carriers in an injectable 25% poloxamer gel were used to investigate the release properties of ibuprofen. Poloxamer gel was also used for the epidural injection of lidocaine and ibuprofen. Biodegradable matrices such as poly lactic acid (PLA) were also used for the controlled release of analgesics. Gel-yielding egg albumin-based matrices were used to study drug release kinetics. Other sustained release formulations consisted of hydroxpropyl methylcellulose (HPMC) matrices or matrices of synthetic crosslinked polymeric resins, as for example crosslinked poly acrylic acid.
It is estimated that 30 to 50% of the women of childbearing age in the US, are affected by painful menstrual periods or dysmenorrhea and 10 to 15% of those women are incapacitated for 1 to 3 days each month. The chief symptom that women experience is spasmodic pain of the lower abdomen, which may radiate to the back and along the thighs.
The etiology of these symptoms has been determined to be related to the pharmacologic actions of prostaglandin E2(PGE2) and prostaglandin F2α (PGF2α), which are formed from phospholipids of dead cell membranes in the menstruating uterus. PGE2 causes disaggregation of platelets and is a vasodilator, whereas PGF2α mediates or potentiates pain sensations and stimulates smooth muscle contraction.
NSAIDs are successful as analgesics in 77 to 80% of dysmenorrhea patients, ibuprofen, naproxen, or naproxen sodium being the usual initial choices.